Local growth hormone promotes benign prostatic hyperplasia
Masaki Ryuzaki, Svetlana Zonis, Neil A. Bhowmick, Sandrine Billet, Saravana Kumar Kailasam Mani, Stephen J. Freedland, Hyung L. Kim, Vera Chesnokova, Shlomo Melmed
Masaki Ryuzaki, Svetlana Zonis, Neil A. Bhowmick, Sandrine Billet, Saravana Kumar Kailasam Mani, Stephen J. Freedland, Hyung L. Kim, Vera Chesnokova, Shlomo Melmed
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Research Article Aging Endocrinology

Local growth hormone promotes benign prostatic hyperplasia

Abstract

Locally produced nonpituitary growth hormone (npGH) promotes DNA damage accumulation and epithelial-mesenchymal transition (EMT) in aging human colon epithelium. GH receptor (GHR) and npGH are expressed in normal human prostate, and benign prostatic hyperplasia (BPH) prevalence increases with age. We hypothesized that local prostate GH action may promote EMT and contribute to BPH pathogenesis. We show here that the number of patients expressing npGH increases more than 10-fold after age 60, concordant with increased γH2AX, a marker of DNA damage, and EMT activation. GH-treated human primary prostate epithelial cells, normal prostate cells, and primary cell cultures derived from resected BPH specimens exhibited enhanced DNA damage and activated EMT, with induced TWIST2, suppressed E-cadherin, and increased Ki67, cell motility, and proliferation. In mice, prostate tissue adjacent to allografted GH-expressing fibroblasts showed increased γH2AX, TWIST2, and Ki67, along with morphological changes consistent with BPH. While GH and GH-induced IGF-1 both activated EMT, GH triggered DNA damage independently of IGF-1. These results elucidate what we believe to be a novel role for local npGH in aging prostate tissue, whereby npGH increases DNA damage and promotes EMT to enable a microenvironment favoring BPH development. Prostate GHR signaling may be an attractive therapeutic target for BPH.

Authors

Masaki Ryuzaki, Svetlana Zonis, Neil A. Bhowmick, Sandrine Billet, Saravana Kumar Kailasam Mani, Stephen J. Freedland, Hyung L. Kim, Vera Chesnokova, Shlomo Melmed

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Figure 7

npGH, γH2AX, and TWIST1/2 expression is increased in aged normal human prostate tissue and in BPH.

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npGH, γH2AX, and TWIST1/2 expression is increased in aged normal human p...
(A and B) Representative IHC images of GH expression (brown) in BPH specimens from a 68-year-old patient. (C and D) Percentage of GH-positive normal prostate or BPH (C) epithelium and (D) stroma. Scores of ≥55 for epithelium and ≥32 for stroma were considered positive. Each dot represents 1 patient. Results were analyzed by χ2 test, as shown in Supplemental Figure 7, A and B. (E) Representative IHC images of intranuclear p-STAT expression (brown) in BPH specimen. (F and G) Representative IHC images of γH2AX expression (brown) in BPH specimen from a 64-year-old patient. (H and I) Percentage of γH2AX-positive normal prostate or BPH (H) epithelium and (I) stroma. Scores of ≥22 for epithelium and ≥11 for stroma were considered positive. Each dot represents 1 patient. Results were analyzed by χ2 test, as shown in Supplemental Figure 7, D and E. (J and K) Representative IHC images of TWIST1/2 expression (brown) in BPH specimen from a 70-year-old patient. Magnification, ×10 (A, F, and J) and ×20 (B, G, and K insets). Scale bars: 100 μm. (L) Percentage of TWIST1/2-positive normal prostate or BPH samples. Scores of ≥70 were considered positive. Each dot represents 1 patient. Results were analyzed by χ2 test, as shown in Supplemental Figure 7H. (M and N) DNA damage, EMT, and proliferation protein expression in primary human BPH cultures treated overnight with 100 ng/mL GH. (M) Western blot in cells from a single patient. (N) ImageJ quantification of protein expression normalized to loading controls in cells from 9 patients. Each dot represents 1 patient. Results are shown as mean ± SEM. Results are shown as percentage of control, but statistical testing was performed on raw numbers. Results were analyzed by 2-tailed Student’s t test. *P < 0.05, **P < 0.01 versus control. Patient characteristics are shown in Table 1.